Malaria, caused by the protozoan parasite Plasmodium falciparum, remains a major global health problem that kills almost one million people each year. Artemisinin and its derivatives are currently the most effective treatment against multi-drug resistant Plasmodium species and artemisinin combination treatments (ACTs) are now first-line drugs (World Malaria Report 2010, WHO Geneva, 2010). Artemisinin belongs to the group of sesquiterpenes and has an uncommon trioxane ring structure and a peroxide bridge.
Artemisinin has a poor bioavailability. Therefore, artemisinin derivatives such as artemether, arteether, artelinic acid and artesunate have been developed. Dihydroartemisinin (DHA or arteminol) is also used as an antimalarial drug. Dihydroartemisinin is available as a fixed drug combination with piperaquine. Artemether, arteether (Artemotil) and artelinic acid are ether derivatives of artemisinin. Artemether and arteether have more potential as compared to artemisinin and are ideal antimalarial drugs, especially for treating multi drug resistant and complicated strains of Plasmodium falciparum. 
Artesunate is an ester derivative of artemisinin that is water-soluble and may therefore be given by injection. According to WHO intravenous artesunate is the drug of choice for severe malaria both in children and adults where there is low transmission.
Artesunate is hydrolyzed within minutes to its active metabolite, dihydroartemisinin, which is considered to be responsible for the antimalarial activity. In vitro data provide evidence for CYP2A6 as the major metabolizing enzyme for artesunate. Artemether is rapidly demethylated to the active metabolite dihydroartemisinin (DHA) by CYP3A4 and CYP3A5.
In vitro studies using human recombinant cytochrome P450 enzymes showed that primarily CYP3A4 is involved in the metabolism of arteether to its active metabolite, dihydroartemisinin (DHA).
Some synthetic methods of ether derivatives of artemisinin are known. U.S. Pat. No. 6,750,356 discloses a single pot conversion of artemisinin to arteether. Artemisinin is reduced to dihydroartemisinin by sodium borohydride in presence of polyhydroxy catalyst and conversion to arteether is carried out in presence of acid catalyst. But this method is time consuming and tedious as it involves purification step by column chromatography.
WO 2008087666 A1 discloses another synthetic method for synthesis of the ether derivative of artemisinin. In this method, artemisinin is reduced to dihydroartemisinin by a mixture of sodium borohydride and a dihydroxy compound. Etherification is carried out in presence of an acid catalyst and an alcohol. After isolating the alpha and beta compounds, recrystallization is to be performed in a hydroalcoholic solution to obtain pure beta ether compound.
WO 2008087667 A1 discloses a method for synthesis of artesunate from artemisinin in one-pot. This method comprises reducing artemisinin to dihydroartemisinin with a mixture of sodium borohydride and a dihydroxy compound; esterifying dihydroartemisinin in the presence of succinic anhydride and imidazole or its derivative as a catalyst in an aprotic solvent and isolating the artesunate by crystallization.
Intending to utilize continuous flow chemistry as a means to scale-up photochemical transformations the inventors examined the transformation of artemisinic acid (1) or dihydroartemisinic acid (2) to artemisinin (3) mindful of the necessity to create a simple, scalable and inexpensive process.
The above-mentioned conversion reactions in the state of art from artemisinin to artemisinin derivatives are performed with batch methods. As already mentioned, batch method has disadvantages such as scale-up, high cost and elaborate purification steps. Most of all in the state of the prior art, for producing each of artemisinin derivative, respective batch procedure and corresponding batch equipment are necessary.
In the state of the art so far only batch methods are known for the synthesis of ester and ether derivatives of artemisinin. However it has been found that the reduction of artemisinin to dihydroartemisinin and further conversion of the dihydroartemisinin to ether or ester derivatives is quite problematic when a certain scale is reached.
Thus objective of the present invention is to provide a more efficient method for the reduction of artemisinin as well as for the synthesis of artemisinin derivatives. The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.